Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology

BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detect...

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Autores: Suarez-Calvet, M, Morenas-Rodriguez, E, Kleinberger, G, Schlepckow, K, Caballero, MAA, Franzmeier, N, Capell, A, Fellerer, K, Nuscher, B, Eren, E, Levin, J, Deming, Y, Piccio, L, Karch, CM, Cruchaga, C, Shaw, LM, Trojanowski, JQ, Weiner, M, Ewers, M, Haass, C, Alzheimers Dis Neuroimaging
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2019
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositório:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p3048
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3048
http://ddd.uab.cat/record/226301
Access Level:Acceso aberto
Palavra-chave:Alzheimer's disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
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spelling Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathologySuarez-Calvet, MMorenas-Rodriguez, EKleinberger, GSchlepckow, KCaballero, MAAFranzmeier, NCapell, AFellerer, KNuscher, BEren, ELevin, JDeming, YPiccio, LKarch, CMCruchaga, CShaw, LMTrojanowski, JQWeiner, MEwers, MHaass, CAlzheimers Dis NeuroimagingAlzheimer's diseaseBiomarkersMicrogliaNeurodegenerationNeuroinflammationSheddingTREM2BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid -peptide (A) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A(1-42) (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.BMC2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3048http://ddd.uab.cat/record/226301Molecular NeurodegenerationISSN: 17501326reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p30482026-06-14T12:41:47Z
dc.title.none.fl_str_mv Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
title Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
spellingShingle Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
Suarez-Calvet, M
Alzheimer's disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
title_short Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
title_full Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
title_fullStr Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
title_full_unstemmed Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
title_sort Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
dc.creator.none.fl_str_mv Suarez-Calvet, M
Morenas-Rodriguez, E
Kleinberger, G
Schlepckow, K
Caballero, MAA
Franzmeier, N
Capell, A
Fellerer, K
Nuscher, B
Eren, E
Levin, J
Deming, Y
Piccio, L
Karch, CM
Cruchaga, C
Shaw, LM
Trojanowski, JQ
Weiner, M
Ewers, M
Haass, C
Alzheimers Dis Neuroimaging
author Suarez-Calvet, M
author_facet Suarez-Calvet, M
Morenas-Rodriguez, E
Kleinberger, G
Schlepckow, K
Caballero, MAA
Franzmeier, N
Capell, A
Fellerer, K
Nuscher, B
Eren, E
Levin, J
Deming, Y
Piccio, L
Karch, CM
Cruchaga, C
Shaw, LM
Trojanowski, JQ
Weiner, M
Ewers, M
Haass, C
Alzheimers Dis Neuroimaging
author_role author
author2 Morenas-Rodriguez, E
Kleinberger, G
Schlepckow, K
Caballero, MAA
Franzmeier, N
Capell, A
Fellerer, K
Nuscher, B
Eren, E
Levin, J
Deming, Y
Piccio, L
Karch, CM
Cruchaga, C
Shaw, LM
Trojanowski, JQ
Weiner, M
Ewers, M
Haass, C
Alzheimers Dis Neuroimaging
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer's disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
topic Alzheimer's disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
description BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid -peptide (A) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A(1-42) (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3048
http://ddd.uab.cat/record/226301
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3048
http://ddd.uab.cat/record/226301
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Molecular Neurodegeneration
ISSN: 17501326
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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